Composition useful for treating disorders related to TRPA1

ABSTRACT

Compounds and compositions for treating disorders related to TRPA1 are described herein.

CLAIM OF PRIORITY

This application is a continuation of U.S. Pat. No. 9,006,207, filedJan. 8, 2013, which is a continuation of U.S. Pat. No. 8,362,025, filedDec. 22, 2009, which claims priority to U.S. Ser. No. 61/139,884, filedDec. 22, 2008, the entire contents of each of which is incorporatedherein by reference.

BACKGROUND

The invention relates to compounds and compositions useful for treatingdisorders related to TRPA1.

A variety of ion channel proteins exist to mediate ion flux acrosscellular membranes. The proper expression and function of ion channelproteins is essential for the maintenance of cell function andintracellular communication. Numerous diseases are the result ofmisregulation of membrane potential or aberrant calcium handling. Giventhe central importance of ion channels in modulating membrane potentialand ion flux in cells, identification of agents that can promote orinhibit particular ion channels are of great interest, both as researchtools and as therapeutic agents.

SUMMARY OF THE INVENTION

The present invention provides compounds and compositions for treatingor preventing conditions such as pain by modulating the activity of theTRPA1 channel. The compounds described herein can modulate the functionof TRPA1 by inhibiting a TRPA1-mediated ion flux or by inhibiting theinward current, the outward current, or both currents mediated by TRPA1.The inhibition of a particular current can be measured by a compound'sability to inhibit or reduce such current (e.g., inward and/or outward)in an in vitro or an in vivo assay. (See Jordt et al. (2004), Nature427:260-265; Bautista et al., (2005) PNAS: 102(34):12248-12252). In oneaspect, the invention features a compound having Formula I, shown below.

In another aspect, the invention features a composition containing anenantiomeric excess (ee) of the compound of Formula I. For example, thecomposition can contain an ee of at least 50%, 75%, 90%, 95%, or 99%.The invention also features salts of the compound made from mineralacids, such as hydrochloric acid, hydrobromic acid, sulfuric acid andphosphoric acid. In one embodiment, the invention features thehydrochloride salt of the compound of Formula I. In one embodiment, theinvention features a composition comprising the hydrochloride salt ofthe compound of Formula I. For example, the composition can contain anee of at least 50%, 75%, 90%, 95%, or 99%.

Any of the compounds disclosed herein may be used to treat any diseasesdisclosed herein. In addition, these compounds may be used to inhibit afunction of a TRPA1 channel in vitro or in vivo.

DETAILED DESCRIPTION OF THE INVENTION

The “enantiomeric excess” or “% enantiomeric excess” of a compositioncan be calculated using the equation shown below. In the example shownbelow a composition contains 90% of one enantiomer, e.g., the Senantiomer, and 10% of the other enantiomer, i.e., the R enantiomer.ee=(90−10)/100=80%.Thus, a composition containing 90% of one enantiomer and 10% of theother enantiomer is said to have an enantiomeric excess of 80%.

Some of the compositions described herein contain an enantiomeric excessof at least 50%, 75%, 90%, 95%, or 99% of Compound 1 (the S-enantiomer).In other words the compositions contain an enantiomeric excess of the Senantiomer over the R enantiomer.

The compounds described herein may also contain unnatural proportions ofatomic isotopes at one or more of the atoms that constitute suchcompounds. For example, the compounds may be radiolabeled withradioactive isotopes, such as for example tritium (³H) or carbon-14(¹⁴C). All isotopic variations of the compounds disclosed herein,whether radioactive or not, are intended to be encompassed within thescope of the present invention. For example, deuterated compounds orcompounds containing ¹³C are intended to be encompassed within the scopeof the invention.

The compound can be useful as the free base or as a salt. Representativesalts include the hydrobromide, hydrochloride, sulfate, bisulfate,phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate,laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate,fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate,lactobionate, and laurylsulphonate salts and the like. (See, forexample, Berge et al. (1977) “Pharmaceutical Salts”, J. Pharm. Sci.66:1-19.)

Certain compounds disclosed herein can exist in unsolvated forms as wellas solvated forms, including hydrated forms. In general, the solvatedforms are equivalent to unsolvated forms and are encompassed within thescope of the present invention. Certain compounds disclosed herein mayexist in multiple crystalline or amorphous forms. In general, allphysical forms are equivalent for the uses contemplated by the presentinvention and are intended to be within the scope of the presentinvention.

An “effective amount” of, e.g., a TRPA1 antagonist, with respect to thesubject methods of inhibition or treatment, refers to an amount of theantagonist in a preparation which, when applied as part of a desireddosage regimen brings about a desired clinical or functional result.Without being bound by theory, an effective amount of a TRPA1 antagonistfor use in the methods of the present invention, includes an amount of aTRPA1 antagonist effective to decrease one or more in vitro or in vivofunctions of a TRPA1 channel. Exemplary functions include, but are notlimited to, membrane polarization (e.g., an antagonist may promotehyperpolarization of a cell), ion flux, ion concentration in a cell,outward current, and inward current. Compounds that antagonize TRPA1function include compounds that antagonize an in vitro or in vivofunctional activity of TRPA1. When a particular functional activity isonly readily observable in an in vitro assay, the ability of a compoundto inhibit TRPA1 function in that in vitro assay serves as a reasonableproxy for the activity of that compound. In certain embodiments, aneffective amount is an amount sufficient to inhibit a TRPA1-mediatedcurrent and/or the amount sufficient to inhibit TRPA1 mediated ion flux.

The term “hydrate” as used herein, refers to a compound formed by theunion of water with the parent compound.

The term “oxidative metabolite” is intended to encompass compounds thatare produced by metabolism of the parent compound under normalphysiological conditions. Specifically, an oxidative metabolite isformed by oxidation of the parent compound during metabolism. Forexample, a thioether group may be oxidized to the correspondingsulfoxide or sulfone.

The term “solvate” as used herein, refers to a compound formed bysolvation (e.g., a compound formed by the combination of solventmolecules with molecules or ions of the solute).

The terms “TRPA1,” “TRPA1 protein,” and “TRPA1 channel” are usedinterchangeably throughout the application. These terms refer to an ionchannel (e.g., a polypeptide) comprising the amino acid sequence setforth in SEQ ID NO: 1, SEQ ID NO:3, or SEQ ID NO: 5 of WO 2007/073505,or an equivalent polypeptide, or a functional bioactive fragmentthereof.

The term “treating” includes prophylactic and/or therapeutic treatments.The term “prophylactic or therapeutic” treatment refers toadministration to the host of one or more of the subject compositions.If it is administered prior to clinical manifestation of the unwantedcondition (e.g., disease or other unwanted state of the host animal)then the treatment is prophylactic, (i.e., it protects the host againstdeveloping the unwanted condition), whereas if it is administered aftermanifestation of the unwanted condition, the treatment is therapeutic,(i.e., it is intended to diminish, ameliorate, or stabilize the existingunwanted condition or side effects thereof).

Indications

Modulating the function of TRPA1 proteins provides a means of modulatingcalcium homeostasis, sodium homeostasis, membrane polarization, and/orintracellular calcium levels, and compounds that can modulate TRPA1function are useful in many aspects, including, but not limited to,maintaining calcium homeostasis, modulating intracellular calciumlevels, modulating membrane polarization, and treating or preventingdiseases, disorders, or conditions associated with calcium and/or sodiumhomeostasis or dyshomeostasis.

Thus, TRPA1 antagonists can be used as part of a prophylaxis ortreatment for a variety of disorders and conditions, described in moredetail below. In other embodiments, the invention provides methods andcompositions for inhibiting a function of a TRPA1 channel in vitro or invivo. The compounds and compositions described herein can be used in thetreatment of any of the foregoing or following diseases or conditions,including in the treatment of pain associated with any of the foregoingor following diseases or conditions.

In certain embodiments, the compounds and compositions disclosed hereincan be used to treat or ameliorate pain. Exemplary classes of pain thatcan be treated include, but are not limited to nociceptive pain,inflammatory pain, and neuropathic pain. The pain can be chronic oracute.

TRPA1 inhibitors may be particularly useful in the treatment of painassociated with cancer, osteoarthritis, rheumatoid arthritis,post-herpetic neuralgia, burns, and other indications detailed above andbelow.

The compounds and compositions disclosed herein may also be used inconnection with prevention or treatment of sensitivity to pain andtouch. Pain or sensitivity to pain and touch may be indicated in avariety of diseases, disorders or conditions, including, but not limitedto, diabetic neuropathy, breast pain, psoriasis, eczema, dermatitis,burn, post-herpetic neuralgia (shingles), peripheral neuropathic andcentral neuropathic pain, cancer and tumor pain, spinal cord injury,crush injury and trauma induced pain, migraine, cerebrovascular andvascular pain, sickle cell disease pain, rheumatoid arthritis pain,musculoskeletal pain including treating signs and symptoms ofosteoarthritis and rheumatoid arthritis, orofacial and facial pain,including dental pain, temperomandibular disorder, and cancer related,lower back or pelvic pain, surgical incision related pain, inflammatoryand non-inflammatory pain, visceral pain, psychogenic pain and softtissue inflammatory pain, reflex sympathetic dystrophy, and painresulting from kidney stones or urinary tract infection.

The compounds and compositions described herein may also be used totreat oral pain. The term “oral pain” refers to any pain in the mouth,throat, lips, gums, teeth, tongue, or jaw. The term is used regardlessof the cause of the pain and regardless of whether the oral pain is aprimary or secondary symptom of a particular disease, injury, orcondition.

The oral pain can be caused by ulcers, sores, or other lesions in themouth. For example, oral pain may be caused by ulcers, sores, or otherlesions on the tongue, gums, lips, throat, or other tissues of themouth. Alternatively or additionally, oral pain may be caused byinflammation of the throat, tongue, gums, lips, or other tissues of themouth. Inflammation may accompany ulcers or other lesions, orinflammation may occur prior to or in the absence of formation of ulcersor other lesions.

The compounds and compositions disclosed herein can also be useful totreat fibromyalgia (FMS; fibromyalgia syndrome); Complex Regional PainSyndrome (CRPS; also known as chronic regional pain syndrome);respiratory conditions such as obstructive diseases such as chronicobstructive pulmonary disease (COPD), emphysema, chronic bronchitis,asthma (including asthma caused by industrial irritants), cysticfibrosis, bronchiectasis, bronchiolitis, allergic bronchopulmonaryaspergillosis, and tuberculosis; restrictive lung disease includingasbestosis, radiation fibrosis, hypersensitivity pneumonitis, infantrespiratory distress syndrome, idiopathic pulmonary fibrosis, idiopathicpulmonary fibrosis, idiopathic interstial pneumonia sarcoidosis,eosinophilic pneumonia, lymphangioleiomyomatosis, pulmonary Langerhan'scell histiocytosis, and pulmonary alveolar proteinosis; respiratorytract infections including upper respiratory tract infections (e.g.,common cold, sinusitis, tonsillitis, pharyngitis and laryngitis) andlower respiratory tract infections (e.g., pneumonia); respiratory tumorswhether malignant (e.g., small cell lung cancer, non-small cell lungcancer, adenocarcinoma, squamous cell carcinoma, large cellundifferentiated carcinoma, carcinoid, mesothelioma, metastatic cancerof the lung, metastatic germ cell cancer, metastatic renal cellcarcinoma) or benign (e.g., pulmonary hamartoma, congenitalmalformations such as pulmonary sequestration and congenital cysticadenomatoid malformation (CCAM)); pleural cavity diseases (e.g., empyemaand mesothelioma); and pulmonary vascular diseases (e.g, pulmonaryembolism such as thromboembolism, and air embolism (iatrogenic),pulmonary arterial hypertension, pulmonary edema, pulmonary hemorrhage,inflammation and damage to capillaries in the lung resulting in bloodleaking into the alveoli. Other conditions that may be treated includedisorders that affect breathing mechanics (e.g., obstructive sleepapnea, central sleep apnea, amyotrophic lateral sclerosis, Guillan-Barresyndrome, and myasthenia gravis). The present compounds can also beuseful for treating, reducing, or preventing one or more symptomsassociated with respiratory conditions including, for example, shortnessof breath or dyspnea, cough (with or without the production of sputum),coughing blood (haemoptysis), chest pain including pleuritic chest pain,noisy breathing, wheezing, and cyanosis.

The compounds and compositions can be used to treat skin diseases ordisorders that are characterized by epidermal hyperplasia, a conditionin which skin cells both proliferate too rapidly and differentiatepoorly. Such diseases include psoriasis, and basal and squamous cellcarcinomas. Many dermatological disorders are accompanied by itch(pruritus). Pruritus and pain share many mechanistic similarities. Bothare associated with activation of C-fibers, both are potentiated byincreases in temperature and inflammatory mediators and both can bequelled with opiates. Decreasing neuronal excitability, particularlyC-fiber excitability may alleviate pruritus associated with dialysis,dermatitis, pregnancy, poison ivy, allergy, dry skin, chemotherapy andeczema.

The compounds and compositions can be used to treat neurodegenerativediseases and disorders such as Alzheimer's disease (AD), Parkinson'sdisease, Huntington's disease, amyotrophic lateral sclerosis (ALS), andother brain disorders caused by trauma or other insults including aging.

The compounds and compositions provided herein may also be used inconnection with treatment of inflammatory diseases. These diseasesinclude but are not limited to asthma, chronic obstructive pulmonarydisease, rheumatoid arthritis, osteoarthritis, inflammatory boweldisease, glomerulonephritis, neuroinflammatory diseases such as multiplesclerosis, and disorders of the immune system.

The compounds and compositions can be used to treat neuropathy, forexample diabetic neuropathy or other peripheral neuropathies. Inaddition to their use in the treatment of peripheral neuropathies (e.g.,reducing inflammation), the subject inhibitors may also be useful inreducing the pain associated with peripheral neuropathy. They can alsobe used to treat pancreatitis, either acute pancreatitis or chronicpancreatitis.

The compounds and compositions provided herein may also be used inconnection with treatment of malignancies, including, but not limitedto, malignancies of lymphoreticular origin, bladder cancer, breastcancer, colon cancer, endometrial cancer, head and neck cancer, lungcancer, melanoma, ovarian cancer, prostate cancer and rectal cancer, inaddition to skin cancers described above.

In addition, pain associated with cancer or with cancer treatment is asignificant cause of chronic pain. Cancers of the bone, for example,osteosarcoma, are considered exceptionally painful, and patients withadvanced bone cancer may require sedation to tolerate the intense andpersistent pain. Accordingly, TRPA1 antagonists of the inventionrepresent a significant possible therapeutic for the treatment of pain,for example, the pain associated with cancer or with cancer treatment.

The compounds and compositions can be used to treat incontinence; tomodulate the sensation of cool, cold and decreased temperatures thatoften accompany pain; to treat hypertension; oral mucositis (also knownas stomatitis); canker sores, also known as aphthous ulcers (aphthae);gastroesophageal reflux disease, or GERD; gingivostomatitis; oralthrush; glossitis; cutaneous diseases such as lichen planus, pemphigus,pemphigoid, and erythema multiforme; Crohn's disease, ulcerativecolitis, irritable bowel syndrome, celiac sprue, and dermatitisherpetiformis.

The compounds and compositions disclosed herein may be used to helpmanage the pain and discomfort of oral inflammation, lesions, or ulcerscaused by any of these gastrointestinal conditions. In addition, thecompounds can be used to treat psoriasis and basal cell and squamouscell cariconomas, a neurodegenerative disease or disorder, e.g.,Alzheimer's disease (AD), Parkinson's disease, Huntington's disease,amyotrophic lateral sclerosis (ALS), and other brain disorders caused bytrauma or other insults including aging, inflammatory bowel disease,glomerulonephritis, neuroinflammatory diseases, multiple sclerosis, anddisorders of the immune system), cancer (e.g. liposarcoma) or otherproliferative disease, kidney disease and liver disease, a metabolicdisorder such as diabetes. Additional conditions include metabolicdiseases and disorders including obesity and diabetes; liver and kidneydiseases and disorders; aging-related disorders; ATP-related diseases ordisorders including epilepsy, cognition, emesis, asthma, peripheralvascular disease, irritable bowel syndrome, cystitis, depression,aging-associated degenerative diseases, cystic fibrosis, diabetes,rheumatoid diseases, Sjogren's Syndrome, allergies, allergic rhinitis,Fabry's disease, and injuries from chemical warfare agents including,for example, nerve agents, blood agents, blister agents, pulmonaryagents, incapacitating agents, and toxins.

Combination Therapy

The subject compounds can be used alone or in combination with otherpharmaceutically active agents. Examples of such other pharmaceuticallyactive agents include, but are not limited to, anti-inflammatory agents(e.g., NSAIDS, bradykinin receptor antagonists, hormones and autacoidssuch as corticosteroids), anti-acne agents (e.g., retinoids),anti-wrinkle agents, anti-scarring agents, anti-incontinence agents(such as M1-receptor antagonists) anti-emetics (such as NK1antagonists), anti-psoriatic agents, antacids, anti-proliferative agents(e.g., anti-eczema agents, anti-cancer), anti-fungal agents, anti-viralagents, anti-septic agents (e.g., antibacterials), local anaesthetics,anti-migraine agents, keratolytic agents, and other agents used for thetreatment of skin diseases or conditions.

In certain embodiments, a compound of the invention is conjointlyadministered with an analgesic. Suitable analgesics include, but are notlimited to, opioids, glucocorticosteroids, non-steroidalanti-inflammatories, naphthylalkanones, oxicams, para-aminophenolderivatives, propionic acids, propionic acid derivatives, salicylates,fenamates, fenamate derivatives, pyrozoles, and pyrozole derivatives.Examples of such analgesic compounds include, but are not limited to,codeine, hydrocodone, hydromorphone, levorpharnol, morphine, oxycodone,oxymorphone, butorphanol, dezocine, nalbuphine, pentazocine, etodolac,indomethacin, sulindac, tolmetin, nabumetone, piroxicam, acetaminophen,fenoprofen, flurbiprofen, ibuprofen, ketoprofen, naproxen, diclofenac,oxaprozin, aspirin, diflunisal, meclofenamic acid, mefanamic acid,prednisolone, and dexamethasone. Preferred analgesics are non-steroidalanti-inflammatories and opioids (preferably morphine).

In some embodiments, the compounds disclosed herein can be admininsteredin conjunction with a therapeutic whose administration causes pain. Forexample, a TRPA1 antagonist can be administered in conjunction with ananesthetic, to reduce the pain caused by the administration of theanaesthetic. A TRPA1 antagonist can also be administered in conjunctionwith a chemotherapeutic agent, to reduce the pain caused byadministration of the chemotherapeutic agent.

In certain embodiments, a compound of the invention is conjointlyadministered with a non-steroidal anti-inflammatory. Suitablenon-steroidal anti-inflammatory compounds include, but are not limitedto, piroxicam, diclofenac, etodolac, indomethacin, ketoralac, oxaprozin,tolmetin, naproxen, flubiprofen, fenoprofen, ketoprofen, ibuprofen,mefenamic acid, sulindac, apazone, phenylbutazone, aspirin, celecoxiband rofecoxib.

In addition to TRPA1, other TRP channels have been implicated in painreception and/or sensation. For example, certain TRPM channels includingTRPM8 have been implicated in the reception and/or sensation of pain.Accordingly, in certain embodiments, the methods of the presentinvention include treating pain by administering (i) a combination of aselective TRPA1 antagonist and a selective TRPM8 antagonist; (ii) acombination of a selective TRPA1 antagonist, a selective TRPM8antagonist, and one or more of a selective TRPV1 and/or TRPV3antagonist; (iii) a cross-TRP inhibitor that antagonizes a function ofTRPA1 and TRPM8; or (iv) a pan inhibitor that antagonizes a function ofTRPA1, TRPM8, and one or more of TRPV1 and TRPV3.

Pharmaceutical Compositions

While it is possible for a compound disclosed herein to be administeredalone, it is preferable to administer the compound as a pharmaceuticalformulation, where the compound is combined with one or morepharmaceutically acceptable excipients or carriers. The compoundsdisclosed herein may be formulated for administration in any convenientway for use in human or veterinary medicine. In certain embodiments, thecompound included in the pharmaceutical preparation may be activeitself, or may be a prodrug, e.g., capable of being converted to anactive compound in a physiological setting.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

Examples of pharmaceutically acceptable carriers include: (1) sugars,such as lactose, glucose and sucrose; (2) starches, such as corn starchand potato starch; (3) cellulose, and its derivatives, such as sodiumcarboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4)powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients,such as cocoa butter and suppository waxes; (9) oils, such as peanutoil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil andsoybean oil; (10) glycols, such as propylene glycol; (11) polyols, suchas glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters,such as ethyl oleate and ethyl laurate; (13) agar; (14) bufferingagents, such as magnesium hydroxide and aluminum hydroxide; (15) alginicacid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer'ssolution; (19) ethyl alcohol; (20) phosphate buffer solutions; (21)cyclodextrins such as Captisol®; and (22) other non-toxic compatiblesubstances employed in pharmaceutical formulations.

Examples of pharmaceutically acceptable antioxidants include: (1) watersoluble antioxidants, such as ascorbic acid, cysteine hydrochloride,sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2)oil-soluble antioxidants, such as ascorbyl palmitate, butylatedhydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propylgallate, alpha-tocopherol, and the like; and (3) metal chelating agents,such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol,tartaric acid, phosphoric acid, and the like.

Solid dosage forms (e.g., capsules, tablets, pills, dragees, powders,granules and the like) can include one or more pharmaceuticallyacceptable carriers, such as sodium citrate or dicalcium phosphate,and/or any of the following: (1) fillers or extenders, such as starches,lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders,such as, for example, carboxymethylcellulose, alginates, gelatin,polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such asglycerol; (4) disintegrating agents, such as agar-agar, calciumcarbonate, potato or tapioca starch, alginic acid, certain silicates,and sodium carbonate; (5) solution retarding agents, such as paraffin;(6) absorption accelerators, such as quaternary ammonium compounds; (7)wetting agents, such as, for example, cetyl alcohol and glycerolmonostearate; (8) absorbents, such as kaolin and bentonite clay; (9)lubricants, such a talc, calcium stearate, magnesium stearate, solidpolyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and(10) coloring agents.

Liquid dosage forms can include pharmaceutically acceptable emulsions,microemulsions, solutions, suspensions, syrups and elixirs. In additionto the active ingredient, the liquid dosage forms may contain inertdiluents commonly used in the art, such as, for example, water or othersolvents, solubilizing agents and emulsifiers, such as ethyl alcohol,isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol,benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (inparticular, cottonseed, groundnut, corn, germ, olive, castor and sesameoils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fattyacid esters of sorbitan, and mixtures thereof.

Suspensions, in addition to the active compounds, may contain suspendingagents as, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar and tragacanth, and mixturesthereof.

Ointments, pastes, creams and gels may contain, in addition to an activecompound, excipients, such as animal and vegetable fats, oils, waxes,paraffins, starch, tragacanth, cellulose derivatives, polyethyleneglycols, silicones, bentonites, silicic acid, talc and zinc oxide, ormixtures thereof.

Powders and sprays can contain, in addition to an active compound,excipients such as lactose, talc, silicic acid, aluminum hydroxide,calcium silicates and polyamide powder, or mixtures of these substances.Sprays can additionally contain customary propellants, such aschlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, suchas butane and propane.

The formulations may conveniently be presented in unit dosage form andmay be prepared by any methods well known in the art of pharmacy. Theamount of active ingredient which can be combined with a carriermaterial to produce a single dosage form will vary depending upon thehost being treated, the particular mode of administration. The amount ofactive ingredient that can be combined with a carrier material toproduce a single dosage form will generally be that amount of thecompound which produces a therapeutic effect.

Dosage forms for the topical or transdermal administration of a compoundof this invention include powders, sprays, ointments, pastes, creams,lotions, gels, solutions, patches and inhalants. The active compound maybe mixed under sterile conditions with a pharmaceutically acceptablecarrier, and with any preservatives, buffers, or propellants that may berequired.

When the compounds disclosed herein are administered as pharmaceuticals,to humans and animals, they can be given per se or as a pharmaceuticalcomposition containing, for example, 0.1 to 99.5% (more preferably, 0.5to 90%) of active ingredient in combination with a pharmaceuticallyacceptable carrier.

The formulations can be administered topically, orally, transdermally,rectally, vaginally, parentally, intranasally, intrapulmonary,intraocularly, intravenously, intramuscularly, intraarterially,intrathecally, intracapsularly, intraorbitally, intracardiacly,intradermally, intraperitoneally, transtracheally, subcutaneously,subcuticularly, intraarticularly, subcapsularly, subarachnoidly,intraspinally, intrasternally or by inhalation.

Dosages

Actual dosage levels of the active ingredients in the pharmaceuticalcompositions of this invention may be varied so as to obtain an amountof the active ingredient that is effective to achieve the desiredtherapeutic response for a particular patient, composition, and mode ofadministration, without being toxic to the patient.

The selected dosage level will depend upon a variety of factorsincluding the activity of the particular compound disclosed hereinemployed, or the ester, salt or amide thereof, the route ofadministration, the time of administration, the rate of excretion of theparticular compound being employed, the duration of the treatment, otherdrugs, compounds and/or materials used in combination with theparticular compound employed, the age, sex, weight, condition, generalhealth and prior medical history of the patient being treated, and likefactors well known in the medical arts.

A physician or veterinarian having ordinary skill in the art can readilydetermine and prescribe the effective amount of the pharmaceuticalcomposition required. For example, the physician or veterinarian couldstart doses of the compounds of the invention employed in thepharmaceutical composition at levels lower than that required in orderto achieve the desired therapeutic effect and gradually increase thedosage until the desired effect is achieved.

In general, a suitable daily dose of a compound of the invention will bethat amount of the compound that is the lowest dose effective to producea therapeutic effect. Such an effective dose will generally depend uponthe factors described above. Generally, intravenous,intracerebroventricular and subcutaneous doses of the compounds of thisinvention for a patient will range from about 0.0001 to about 100 mg perkilogram of body weight per day. If desired, the effective daily dose ofthe active compound may be administered as two, three, four, five, sixor more sub-doses administered separately at appropriate intervalsthroughout the day, optionally, in unit dosage forms. In someembodiments, the dose will be 1-20, or 5-10 mg per kilogram of bodyweight, administed twice daily.

EXAMPLES

The following examples are intended to be illustrative, and are notmeant in any way to be limiting.

Example 1 Synthesis of Compound 1

Step 1: Synthesis of Compound 10(3′-F,4′-[(S)-2-methylpyrrolidino]acetophenone)

A 100 mL 3-necked round-bottomed flask was equipped with an overheadmechanical stirrer, nitrogen inlet and reflux condenser. To potassiumcarbonate, powdered (6.49 g, 47.0 mmol) in the flask was added DMSO (40mL). The solid was gently stirred while (S)-2-methylpyrrolidine, >99%ee, (4.80 ml, 47.0 mmol) and 3,4-difluoroacetophenone (5.35 ml, 42.7mmol) were added. The solid remained free-flowing while the liquidportion turned light yellow. The mixture was heated to 60° C. with anoil bath. After 1 hour, the oil bath temperature was increased to 80° C.LCMS analysis of the reaction mixture after 5 hours indicated thereaction was complete. The reaction mixture was cooled, and poured intoa 250 mL separatory funnel containing 60 mL ethyl ether and 60 mL water.The reaction vessel was rinsed with 30 mL of water and 30 mL of ethylether and the washings were added to the separatory funnel. Aftershaking, the layers were separated, and the aqueous layer wasback-extracted with an additional 60 mL of ethyl ether. The combinedorganic layers were washed with 30 mL water, 60 mL 0.1 M H₃PO₄ (whichremoved some color), 30 mL saturated sodium bicarbonate, 30 mL brine.The solution was dried over sodium sulfate, and concentrated via rotaryevaporation to an amber oil, ˜9.5 g. The solution was passed through aplug of silica gel (60 g), packed into a large fritted filter funnel,topped with sand. The yellow solution was concentrated via rotaryevaporation to give a yellow oil, 9.307 g, 98% yield. Mass spectrum: 222(M+1)⁺.

Step 2: Preparation of Compound 12

To the product from Step 1 (34.0 g, 154 mmol) in 102 mL of isopropylacetate was added 168 mL of HBr (47%). The addition was exothermic.Bromine (24.55 g, 154 mmol) was added to this mixture at 18-24° C. Themixture was stirred for 4 hours. Analysis by LCMS showed 11.8% startingketone, 81.7% desired mono-brominated product, and 6.4% di-brominatedproduct. The reaction mixture was added to a mixture of 480 mL water and340 mL dichloromethane at 5-10° C. The mixture was stirred and warmed to18-24° C. The phases were separated and the organic phase was washedwith 100 mL of saturated sodium bicarbonate solution. Subsequently theorganic phase was washed twice with 50 mL of water each time. Thesolution was concentrated under vacuum to yield Compound 12 as an oil(42.8 g, 92.3%). Mass spectrum: 300, 302 (M+1)⁺.

Step 3: Preparation of4-(3-F,4-(S)-2-methylpyrrolidinophenyl)aminothiazole hydrobromide

The product of Step 2 (21.1 g, 70 mmol) was dissolved in 106 mLdichloromethane and added to a suspension of thiourea (4.28 g, 56 mmol)in 53 mL of ethanol at 0-5° C. After 1 hr the conversion was complete asdetermined by LCMS and 295 mL of isopropyl acetate was added over 30 minat 0-5° C. The formed suspension was stirred for 2 hrs at 0-5° C. Theproduct was filtered and washed with 40 mL isopropyl acetate. Afterdrying under vacuum at 50° C., 18.0 g, 71.4% of the product was isolatedas a off white solid. (Purity 99.44 area %). Mass spectrum: 278 (M+1)⁺.

Step 4

Theophylline-7-acetic acid (17.55 g, 74 mmol) and 0.82 g of4-dimethylaminopyridine were suspended in 72 mL of DMF. A solution of16.29 g, 100 mmol) 1,1′-carbonyldiimidazole in 96 mL of DMF was added at18-24° C. and rinsed with 5 mL of DMF. During stirring for 30 min. aclear solution was formed, which was heated to 50° C. At thistemperature a solution of the product of Step 3 (24 g, 67 mmol) in 120mL of DMF was added. The line was rinsed with 5 mL of DMF. The mixturewas heated for 6.5 hrs at 50° C. and subsequently at room temperaturefor two days. The product suspension was heated to 50° C. and 180 mL ofwater was added. The suspension was cooled to 18-24° C. over about 2hours and filtered. The product was washed with 240 mL of water inportions. Wet product (81.0 g) was isolated. The wet crude product (64g) was suspended in 285 mL of ethanol and heated to reflux for 30 min.The suspension was cooled to room temperature. The product was filteredand washed with 80 mL of ethanol. After drying, 22.0 g (83% yield) ofCompound 1 was isolated. Mass spectrum: 498 (M+1)⁺.

Example 2 Formation of the HCl Salt

Compound 1 (200 mg, 0.402 mmol) was suspended and stirred in aq. HClsolution (1.0 N, 5.0 mL) at 80° C. for 20 h under the atmosphere ofargon. The mixture was cooled to room temperature, then filtered. Thesolid was washed with ethanol (10 mL), then ether (20 mL). The resultingwhite solid was dried in vacuo to give 192 mg of the corresponding HClsalt in 89% yield. m.p. 249° C.

Example 3 Inhibition of TRPA1

Compound 1 was tested using a procedure similar to the procedureoutlined in WO 2007/073505. The IC₅₀ of Compound 1 against hTRPA1channel activity was found to be about 4 nM.

Example 4 Effect of Compound 1 on Formalin-Induced Pain Behavior in Rats

Compound 1 was tested in the formalin-induced pain test reported byDubuisson et al., Pain 1977 December; 4(2):161-74. The compound wasdosed orally in rats (8 animals) at 50 mg/kg, one hour prior tointraplantar formalin (3%) injection. The control group (8 animals)received vehicle (30% Captisol® in water, pH 10). The duration of painbehaviors was observed for 2 minutes following the injection. Theduration of pain behavior in the treated animals was reduced by about30%, compared to the animals who received vehicle.

Example 5 Effect of Compound 1 on AITC-Induced Pain Behavior in the Rat

Compound 1 was tested in the automated flinch detecting system describedby Yaksh et al., J. Appl. Physiol 90: 2386-2402 (2001). A small metalband was loosely placed around each rat's left hind paw. The fasted ratswere dosed (50 mg/kg) via oral gavage with Compound 1 (8 animals) orvehicle (8 animals, 30% Captisol® in water, pH 10). The rats wereacclimatized in the test chamber prior to allyl isothiocyanate (AITC)administration. AITC was then injected into the paw of each animal, andthe animal was promptly returned to the chamber. The number of pawflinches was monitored for 60 minutes. After 10 minutes, animalsreceiving vehicle flinched a total of about 350 times, while the treatedanimals flinched about 200 times. After 60 minutes the animals that hadreceived vehicle prior to AITC administration flinched about 1950 times,while the compound pre-treated animals flinched about 1000 times. Theseresults demonstrate that Compound 1 was able to reduce the AITC-inducedpain behavior in rats.

INCORPORATION BY REFERENCE

All publications and patents mentioned herein are hereby incorporated byreference in their entirety as if each individual publication or patentwas specifically and individually indicated to be incorporated byreference.

EQUIVALENTS

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents to the specificembodiments of the invention described herein. Such equivalents areintended to be encompassed by the following claims.

We claim:
 1. A method for treating a respiratory condition in a human,the method comprising administering an effective amount of a compositioncomprising a compound of Formula I, or a pharmaceutically acceptablesalt thereof:


2. The method of claim 1, wherein the composition contains anenantiomeric excess of at least 50% of a compound of Formula I.
 3. Themethod of claim 1, wherein the composition contains an enantiomericexcess of at least 75% of a compound of Formula I.
 4. The method ofclaim 1, wherein the composition contains an enantiomeric excess of atleast 90% of a compound of Formula I.
 5. The method of claim 1, whereinthe composition contains an enantiomeric excess of at least 95% of acompound of Formula I.
 6. The method of claim 1, wherein the compositioncontains an enantiomeric excess of at least 99% of a compound of FormulaI.
 7. The method of claim 1, wherein the composition contains apharmaceutically acceptable salt of the compound of Formula I.
 8. Themethod of claim 7, wherein the pharmaceutically acceptable salt is ahydrochloride, hydrobromide, sulfate, or phosphate salt of a compound ofFormula I.
 9. The method of claim 1, wherein the respiratory conditioncomprises chronic obstructive pulmonary disease (COPD), emphysema,chronic bronchitis, asthma, cystic fibrosis, bronchiectasis,bronchiolitis, allergic bronchopulmonary aspergillosis, tuberculosis,asbestosis, radiation fibrosis, hypersensitivity pneumonitis, infantrespiratory distress syndrome, idiopathic pulmonary fibrosis, idiopathicinterstial pneumonia sarcoidosis, eosinophilic pneumonia,lymphangioleiomyomatosis, pulmonary Langerhan's cell histiocytosis,pulmonary alveolar proteinosis, common cold, sinusitis, tonsillitis,pharyngitis, laryngitis, or pneumonia.
 10. The method of claim 1,wherein the respiratory condition comprises a respiratory tumor selectedfrom small cell lung cancer, non-small cell lung cancer, adenocarcinoma,squamous cell carcinoma, large cell undifferentiated carcinoma,carcinoid, mesothelioma, metastatic cancer of the lung, metastatic germcell cancer, metastatic renal cell carcinoma, pulmonary hamartoma,pulmonary sequestration ,and congenital cystic adenomatoid malformation(CCAM); empyema; mesothelioma; pulmonary embolism selected fromthromboembolism and air embolism; pulmonary arterial hypertension;pulmonary edema; pulmonary hemorrhage; inflammation; or damage tocapillaries in the lung resulting in blood leaking into the alveoli.